Reverse transcription is a common feature of retrovirus replication. Viral replication requires a virally encoded reverse transcriptase to generate DNA copies of viral sequences by reverse transcription of the viral RNA genome. Reverse transcriptase, therefore, is a clinically relevant target for the chemotherapy of retroviral infections because the inhibition of virally encoded reverse transcriptase would interrupt viral replication
A number of compounds are effective in the treatment the human immunodeficiency virus (HIV) which is the retrovirus that causes progressive destruction of the human immune system with the resultant onset of AIDS. Effective treatment through inhibition of HIV reverse transcriptase is known for both nucleoside based inhibitors, such as azidothymidine, and non-nucleoside based inhibitors. Benzoxazinones have been found to be useful non-nucleoside based inhibitors of HIV reverse transcriptase. The (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-ben zoxazin-2-one of formula (VI): ##STR1## is not only a highly potent reverse transcriptase inhibitor, it is also efficacious against HIV reverse transcriptase resistance. Due to the importance of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-ben zoxazin-2-one as a reverse transcriptase inhibitor, economical and efficient synthetic processes for its production need to be developed.
Cyclopropylacetylene is an important reagent in the synthesis of compound (VI). Thompson et al, Tetrahedron Letters 1995, 36, 937-940, describe the asymmetric synthesis of an enantiomeric benzoxazinone by a highly enantioselective acetylide addition followed by cyclization with a condensing agent to form the benzoxazinone shown below. ##STR2## As a reagent the cyclopropylacetylene was synthesized in a 65% yield by cyclization of 5-chloropentyne with n-butyllithium at 0.degree.-80.degree. C. in cyclohexane followed by quenching with ammonium chloride. The process generates a low yield of cyclopropylacetylene which is not feasible for the large commercial process of a difficult to handle reagent.
Thompson et al, PCT International Patent Application Number WO 9622955 A1 describe an improved synthesis of cyclopropylacetylene useful in the synthesis of (S)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-ben zoxazin-2-one. Application Wo 9622955 Al discloses methods which continue to be inefficient in the overall synthesis on a kilogram scale for which this invention makes significant improvements. Application WO 9622955 A1 does not teach the improvement of concentrating cyclopropylacetylene into a high boiling solvent.
The chemical literature shows the majority of the cyclopropylacetylene preparations involve the conversion of cyclopropylmethyl ketone to cyclopropyl-acetylene via the following chemical scheme. ##STR3##
The above method will produce cyclopropylacetylene on small scale, &lt;1 kilogram, but is not amenable for bulk production, thus an alternative was developed.
The above methods for the synthesis of cyclopropyl-acetylene use combinations of toxic, difficult to handle reagents, relatively expensive materials, incomplete conversions and low yields which render the overall synthesis inefficient and yield cyclopropylacetylene of lower purity. Thus, it is desirable to discover new synthetic routes to cyclopropylacetylene on a large scale which improve upon these limitations and provide high yields of desired cyclopropylacetylene.
Accordingly, the present invention provides for a novel scalable procedure starting with 5-halo-1-pentyne, wherein the conversion of pentyne to cyclopropylethyne is greater than 95%, the overall yield is greater than 90%, the purification of a difficult and tedious volatile product is simplified and the cyclopropylacetylene product is free of acidic materials. The purification and high yield has been simplified by the addition of a concentration step after cyclization of 5-halopentyne into a cyclopropylacetylide anion. This modification allows for the concentration of the volatile cyclopropylacetylene as its non-volatile cyclopropylacetylide salt form. Furthermore, the addition of a concentration step imparts an unexpected safety benefit in the handling of organolithium compounds due to their general explosive and pyrophoretic properties.
Optimization of the procedure allows for streamlined processing since the product does not require isolation. The present invention provides the preparation of cyclopropylacetylene as such pure product that it may be used as a solution stream reagent in the addition of lithium cyclopropylacetylide to any other reagent in synthesis.
None of the above-cited references describe the methods of the present invention for the synthesis of cyclopropylacetylene.